Solid tumor masses in cancer patients have been found to be heterogeneous in oxygenation and to contain regions of hypoxia. See Vaupel, P., "Oxygenation of Human Tumors", Strahlenther, Onkol. 166:377-386 (1990); and Adams, G. E., The Clinical Relevance of Tumour Hypoxia, 26(4):420-421 (1990). Recent studies in human tumors with oxygen electrodes have reaffirmed the occurrence of significant hypoxic areas within human tumors. Vaupel, P. ibid; Kallinowski, F. et al., "Tumor Tissue Oxygenation as Evaluated by Computerized-pO.sub.2 -Histography", Int. J. Radiat. Oncol. Biol. Phys. 19:953-961 (1990); and Gatenby, R. A. et al., "Oxygen Distribution in Squamous Cell Carcinoma Metastases and Its Relationship to Outcome of Radiation Therapy", Int. J. Radiat. Oncol. Biol. Phys. 14:831-838 (1988). Preclinical studies, both in vitro and in vivo, have established that hypoxia protects tumor cells from the cytoxic actions of radiation and chemotherapeutic agents and thereby may be a significant factor in therapeutic resistance. Adams, G. E. ibid; Sartorelli, A. C., "Therapeutic Attack of Hypoxic Cells of Solid Tumors: Presidential Address", Cancer Res. 48: 775-778 (1988); Teicher, B. A. et al., "Classification of Antineoplastic Agents by Their Selective Toxicities Toward Oxygenated and Hypoxic Tumor Cells", Cancer Res. 41:73-81 (1981); and Teicher, B. A. et al., "Classification of Antineoplastic Treatments by Their Differential Toxicity Toward Putative Oxygenated and Hypoxic Tumor Subpopulations in vivo in the FSaIIC Murine Fibrosarcoma", Cancer Res. 50:3339-3344 (1990).
Increased delivery of oxygen from the lungs can be a useful way of improving the oxygenation of solid tumor masses by altering the gradient of oxygen as it is absorbed from the vasculature and distributed into the tissue. Because of this, one strategy which has been attempted to overcome the problem of hypoxia in treating tumors involves the use of perfluorocarbon emulsions with oxygen or carbogen (95% oxygen/5% carbon dioxide) breathing. Holden, S. A. et al., "Addition of a Hypoxic Cell Selective Cytotoxic Agent (mitomycin C or porfiromycin) to Treatment with Fluosol-DA.RTM./Carbogen/Radiation", Radiother. Oncol. 18:59-70 (1990); Teicher, B. A. et al., "The Effect of Fluosol-DA and Oxygenation Status on the Activity of Cyclophosphamide In Vivo" Cancer Chemother. Pharmacol. 21:286-291 (1988); Martin, D. F. et al., "Enhancement of Tumor Radiation Response by the Combination of a Perfluorochemical Emulsion and Hyperbaric Oxygen", Int. J. Radiat. Oncol. Biol. Phys. 13:747-751 (1987); Teicher, B. A. and C. M. Rose, "Perfluorochemical Emulsion Can Increase Tumor Radiosensitivity"Science 223:934-936 (1984 ); and Teicher, B. A. et al., "Optimization of Perfluorochemical levels with Radiation Therapy" Cancer Res. 49:2693-2697 (1989). In preclinical solid tumor models, the use of perfluorocarbon emulsions with carbogen or oxygen breathing in conjunction with radiation therapy has produced positive results. Teicher, B. A. and C. M. Rose ibid; Teicher, B. A. et al., ibid; Teicher, B. A. and C. M. Rose, "Oxygen-Carrying Perfluorochemical Emulsion as an Adjuvant to Radiation Therapy in Mice", Cancer Res. 44:4285-4288 (1984); Teicher, B. A. and C. M. Rose, "Effect of Dose and Scheduling on Growth Delay of the Lewis Lung Carcinoma Produced by the Perfluorochemcial Emulsion, Fluosol-DA", Int. J. Radiat. Oncol. Biol. Phys. 12:1311-1313 (1986); Teicher, B. A. et al., "Influence of Scheduling Dose and Volume of Administration of the Perfluorochemical Emulsion Therox.RTM. on Tumor Response to Radiation Therapy", Int. J. Radiat. Oncol. Biol. Phys., in press (1991); Teicher, B. A. et al., "Effect of Fluosol.RTM.-DA on the Response of Intracranial 9L Tumors to X-rays and BCNU", Int. J. Radiat. Oncol. Biol. Phys. 15:1187-1192 (1988); Lee. I. et al., "Effects of Fluosol-DA and Carbogen on the Radioresponse of SCK Tumors and Skin of A/J Mice", Radiat. Res. 112:173-182 (1987); Martin, D. F. et al., "Effect of a Perfluorochemical Emulsion on the Radiation Response of BA 1112 Rhabdomysarcomas", Radiat. Res. 112:45-53 (1987); Moulder, J. E. et al., "Applicability of Animal Tumor Data to Cancer Therapy in Humans", Int. J. Radiat. Oncol. Biol. Phys. 14:913-927 (1988); Moulder, J. E. and B. L. Fish, "Tumor Sensitization by the Intermittent use of Perfluorochemical Emulsions and Carbogen Breathing in Fractionated Radiotherapy", In: E. M. Fielden, J. F. Fowler, J. H. Hendry and D. Scott (eds.), Proceedings of the 8th International Congress of Radiation Research, Vol. 1, p. 299, London: Taylor and Francis, Inc. (1987); Rockwell, S. et al., "Reactions of Tumors and Normal Tissues in Mice to Irradiation in the Presence and Absence of a Perfluorochemical Emulsion" int. Radiat. Oncol. Biol. Phys. 112:1315-1318 (1986); Song. C. W. et al., "Increase in pO.sub.2 and Radiosensitivity of Tumors by Fluosol.RTM.-DA (20%) and Carbogen", Cancer Res. 47:442-446 (1987); and Zhang. W. L. et al., "Enhancement of Tumor Response to Radiation by Fluosol-DA", Int. J. Radiat. Oncol. Biol. Phys. 10:172-175 (1984).
Further, some initial clinical trials of the perfluorochemical emulsion, Fluosol.RTM.-DA and oxygen breathing with radiation therapy have been carried out and some are still underway. Rose, C. M. et al., "A Clinical Trial of Fluosol.RTM.-DA 20% in Advanced Squamous Cell Carcinoma of the Head and Neck", Int. J. Radiat. Oncol, Biol. Phys. 12:1325-1327 (1986); Lustig, R. et al., "Phase I-II Study of Fluosol-DA and 100% Oxygen Breathing as an Adjuvant to Radiation in the Treatment of Advanced Squamous Cell Tumors of the Head and Neck", Int. J. Radiat. Oncol. Biol. Phys. 16:1587-1594 (1989); Lustig, R. et al., "Phase I/II Study of Fluosol and 100% Oxygen Breathing as an Adjuvant to Radiation in the Treatment of Unresectable Non Small Cell Carcinoma of the Lung", Int. J. Radiat. Oncol. Biol. Phys. 17sl:202 (1989); and Evans, R. G. et al., "A Phase I-II Study of the Use of Fluosol.RTM.-DA 20% as an Adjuvant of Radiation Therapy in the Treatment of Primary High-Grade Brain Tumors" , Int. J. Radiat. Oncol. Biol. Phys. 1721:175 (1989).
The effect of perfluorocarbon emulsions in carbogen or oxygen breathing with certain chemotherapeutic agents has also been studied in preclinical solid tumor models. Teicher, B. A. et al., "Classification of Antineoplastic Treatments by Their Differential Toxicity Toward Putative Oxygenated and Hypoxic Tumor Subpopulations in vivo in the FSaIIC Murine Fibrosarcoma", Cancer Res. 50:3339-3344 (1990); Holden, S. A. et al., "Addition of a Hypoxic Cell Selective Cytotoxic Agent (Mitomycin C or Porfiromycin) to Treatment with Fluosol-DA.RTM. Carbogen/Radiation", Radiother. Oncol. 18:59-70 (1990); Teicher, B. A. et al., "The Effect of Fluosol-DA and Oxygenation Status on the Activity of Cyclophosphamide in vivo" Cancer Chemother. Pharmacol. 21:286-291 (1988); Teicher, B. A. et al., "Approaches to Defining the Mechanism of Fluosol-DA 20%/Carbogen Enhancement of Melphalan Antitumor Activity", Cancer Res. 47:513-518 (1987); Teicher, B. A. et al., "Differential Enhancement of Melphalan Cytotoxicity in Tumor and Normal t+Tissue by Fluosol-DA and Oxygen Breathing", Int. J. Cancer 36:585-589 (1985); Teicher, B. A. et al., "Effects of Various Oxygenation Conditions on the Enhancement by Fluosol-DA of Melphalan Antitumor Activity", Cancer Res. 47:5036-5041 (1987); Teicher, B. A. and S. A. Holden, "A Survey of the Effect of Adding Fluosol-DA 20%/O.sub.2 to Treatment with Various Chemotherapeutic Agents", Cancer Treat. Rep. 71:173-177 (1987); Teicher, B. A. et al., "Effect of Various Oxygenation Conditions and Fluosol-DA on Cancer Chemotherapeutic Agents", Biomat., Art. Cells and Art. Organs 16:533-546 (1988); Teicher, B. A. et al., "Effect of Oxygen on the Cytotoxicity of Antitumor Activity of Etoposide", J. Natl. Cancer Inst. 75:1129-1133 (1985); Teicher, B. A. et al., "Effect of Fluosol-DA/O.sub.2 on Tumor Cell and Bone Marrow Cytotoxicity of Nitrosoureas in Mice Bearing FSaII Fibrosarcoma", Int. J. Cancer 38:285-288 (1986); Teicher, B. A. et al., "Effect of Fluosol-DA/O.sub.2 on the Antitumor Activity and Pulmonary Toxicity of Bleomycin", Cancer Chemother. Pharmacol. 18:213-218 (1986); Teicher, B. A. et al., "Effects of Fluosol.RTM.-DA and Oxygen Breathing on Adriamycin Antitumor Activity and Cardiac Toxicity in Mice", Cancer 61:2196-2201 (1988); Teicher, B. A. et al., "Effect of Carious Oxygenation Conditions and Fluosol.RTM.-Da on the Cytotoxicity and Antitumor Activity of Bleomycin", J. Natl. Cancer Inst. 80:599-603 (1988); Teicher, B. A. et al., "Effect of Fluosol-DA/Carbogen on Etoposide/Alkylating Agent Antitumor Activity", Cancer Chemother. Pharmacol. 21:281-285 (1988); Martin, D. F. et al., "Potentiation of Rat Brain Tumor Therapy by Fluosol and Carbogen", NCI Monogr. 6:119-122 (1988); and Kim. G. E. and C. W. Song, "The Influence of Fluosol-DA and Carbogen Breathing on the Antitumor Effects of Cyclophosphamide In Vivo", Cancer Chemother. Pharmacol. 25:99-102 (1989). With many chemotherapeutic agents, very positive therapeutic results have been obtained and several initial clinical trials have been carried out with Fluosol-DA and oxygen breathing with single anticancer drugs. See Gruber, M. et al., "Phase I/II Study of Fluosol.RTM./O.sub.2 in Combination with BCNU in Malignant Glioma", Proc. Amer. Assoc. Cancer Res. 31:190 (March 1990); Carewal, H. et al., "Fluosol.RTM./Oxygen in Combination with Cyclophosphamide in Advanced Non-Small Cell Lung Carcinoma (NSCLC): Phase I Results", Proc. Amer. Assoc. Cancer Res. 30:271 (March 1989); and Meyers, F. et al., "Phase I/II Study of Fluosol.RTM./Oxygen in Combination with Weekly 5-Fluorouracil (5FU) in Metastatic Colorectal Carcinoma", Proc. Amer. Assoc. Cancer Res. 30:256 (March 1989).
Despite the initial success with the use of perfluorocarbon emulsions and carbogen or oxygen breathing in conjunction with ionizing radiation, these techniques have not proven entirely satisfactory. For example, perfluorocarbons have very limited oxygen-transport capability at ambient oxygen pressures. Blood delivers approximately 6% (v/v) oxygen to tissues at ambient pressures, whereas, at these same pressures, perfluorocarbon emulsions can only deliver about 2% (v/v).